Kenneth P. Batts

Chronic hepatitis. An update on terminology and reporting.

The terms chronic active hepatitis (CAH), chronic persistent hepatitis (CpH), and chronic lobular hepatitis (CLH) have become obsolete, and their use without further specifications should be discontinued. This recommendation has become necessary because these names have changed from descriptive terms, intended for grading, to terms that are used either as morphologic diagnoses or disease designations or both, depending on individual preferences. Because this practice has caused serious misunderstandings, many authors and two international groups have recommended the use of a clear etiologic terminology. For the reporting practice of pathologists, we recommend that the pathologist routinely sign out biopsy samples with features of chronic hepatitis by indicating etiology, grade, and stage. An example would be autoimmune hepatitis, severe, stage 3. The stage in this case would indicate the presence of well-developed septal fibrosis but no nodular regeneration. Obviously, for the etiologic diagnosis, morphologic findings must be integrated with clinical and laboratory data. If this information is not available, clear morphologic diagnoses should be reported. Thus, instead of CPH, the diagnosis should be portal hepatitis, cause undetermined. This reporting practice eliminates ambiguous terminology and avoids the risk of inappropriate treatment as might occur, for example, when a term such as CAH is used to describe Wilsons disease and is misunderstood to mean autoimmune hepatitis. For a transitional period and to facilitate relearning, the terms CAH, CPH, and CLH can be reported in parentheses behind the etiologic diagnosis.

Serrated Lesions of the Colorectum: Review and Recommendations From an Expert Panel

Serrated lesions of the colorectum are the precursors of perhaps one-third of colorectal cancers (CRCs). Cancers arising in serrated lesions are usually in the proximal colon, and account for a disproportionate fraction of cancer identified after colonoscopy. We sought to provide guidance for the clinical management of serrated colorectal lesions based on current evidence and expert opinion regarding definitions, classification, and significance of serrated lesions. A consensus conference was held over 2 days reviewing the topic of serrated lesions from the perspectives of histology, molecular biology, epidemiology, clinical aspects, and serrated polyposis. Serrated lesions should be classified pathologically according to the World Health Organization criteria as hyperplastic polyp, sessile serrated adenoma/polyp (SSA/P) with or without cytological dysplasia, or traditional serrated adenoma (TSA). SSA/P and TSA are premalignant lesions, but SSA/P is the principal serrated precursor of CRCs. Serrated lesions have a distinct endoscopic appearance, and several lines of evidence suggest that on average they are more difficult to detect than conventional adenomatous polyps. Effective colonoscopy requires an endoscopist trained in the endoscopic appearance of serrated lesions. We recommend that all serrated lesions proximal to the sigmoid colon and all serrated lesions in the rectosigmoid >5 mm in size, be completely removed. Recommendations are made for post-polypectomy surveillance of serrated lesions and for surveillance of serrated polyposis patients and their relatives.

Hepatic resection for metastatic neuroendocrine carcinomas

BACKGROUND Metastatic neuroendocrine malignancies frequently cause incapacitating endocrinopathies, and metastases predominant in the liver. Hepatic resection of metastases from such tumors is attractive because the natural history of neuroendocrine tumors is protracted, clinical severity of the endocrinopathy correlates with tumor volume, and local and intrahepatic growth characteristics often allow complete resection. PATIENTS AND METHODS To define the role of hepatic resection for metastatic neuroendocrine tumors, the records of 74 patients who underwent hepatic resection for such tumors between 1984 and 1992 were reviewed. Neuroendocrine tumors were classified by site of origin and clinical endocrinopathy. Survival, and type and duration of symptomatic response, were assessed as the major outcomes of this study. RESULTS There were 50 carcinoid, 23 islet-cell, and 1 atypical neuroendocrine tumors. Resections included 36 hemihepatectomies or extended hepatectomies and 38 nonanatomic resections. Thirty-eight primary tumors were resected concomitantly. Perioperative mortality was 2.7% and morbidity was 24%. Four-year survival was 73%. Overall postoperative symptomatic response rate was 90% with a mean duration of response of 19.3 months. CONCLUSIONS Hepatic resection for metastatic neuroendocrine malignancies is safe, provides effective palliation, and probably prolongs survival.

Serrated Polyps of the Large Intestine A Morphologic and Molecular Review of an Evolving Concept

Serrated polyps of the large intestine, including traditional hyperplastic polyps, traditional serrated adenomas, and more recently described sessile serrated adenomas, have gained increased recognition in recent years because of growing evidence that one of these lesions, the sessile serrated adenoma, might be the precursor lesion for some cases of microsatellite unstable colorectal carcinoma. Nevertheless, there has been some reluctance to embrace the concept of sessile serrated adenoma, and numerous diagnostic challenges exist. This article, which grew out of the Roger C. Haggitt Gastrointestinal Pathology Society Forum presented in Vancouver, Canada, March 6, 2004 as part of the annual meeting of the United States-Canadian Academy of Pathology, reviews the morphologic and molecular evidence for the concept of various polyps in the general category of serrated polyps of the large intestine, in particular the lesion known as the sessile serrated adenoma, and provides a conceptual framework for diagnosis of these lesions.

Use of fatty donor liver is associated with diminished early patient and graft survival.

It is well known that implantation of donor livers with severe fatty infiltration (>60%) is frequently associated with early hepatic dysfunction and an increased incidence of primary nonfunction after liver transplantation. The outcome of donor livers with less fatty infiltration has not been well defined. We, therefore, studied the outcome of 59 liver transplantations in which donor livers with up to 30% fat were used. Patient outcome was compared to a time-matched control group of 57 patients. The two groups were similar in terms of age, gender, preservation time, primary diagnosis, and UNOS status. We compared both groups with regard to 4-month and 2-year patient and graft survival. We also assessed the incidence of ischemic type biliary strictures and hepatic artery thrombosis, and evaluated the causes of graft loss in both groups. We found that use of donor livers with up to 30% fatty infiltration was associated with a significant decrease in 4-month graft survival (76% vs. 89%, P<0.05) and in 2-year patient survival (77% vs. 91%, P<0.05). Primary nonfunction and primary dysfunction formed the main cause of graft loss and mortality. Multivariate analysis showed that fatty infiltration is an independent predictive factor for outcome after transplantation. We conclude that liver allografts with up to 30% fat lead to diminished outcome after liver transplantation. However, this diminished outcome should be viewed with respect to the increasing mortality on the national waiting list.

Complete ablation of esophageal epithelium with a balloon-based bipolar electrode: a phased evaluation in the porcine and in the human esophagus

BACKGROUND The aim of this study was to evaluate the endoscopic and the histologic effects of a balloon-based bipolar radiofrequency electrode for ablation of porcine and human esophageal epithelium. METHODS All procedures were performed with a balloon-based, bipolar radiofrequency system that creates a circumferential, thin-layer epithelial ablation zone within the esophagus. In Phase I, multiple ablations were created in 10 farm swine, followed by acute euthanasia and histologic assessment for completeness of epithelial removal and ablation depth. In Phase II, multiple ablations were created in 19 farm swine, with varying power and energy density, followed by endoscopy at 2 and 4 weeks to assess stricture formation. In Phase III, 3 ablations were created in 12 farm swine, with varying energy density (5, 8, 10, 12, 15, or 20 J/cm 2 ) at 350 W. Animals were euthanized at 48 hours. Histologic examination determined the percentage of epithelium removed and the ablation depth. In Phase IV, 3 patients underwent esophageal epithelial ablation before esophagectomy, creating separate lesions proximal to the tumor. Completeness of epithelial ablation and ablation depth was quantified histologically. RESULTS In Phase I, complete removal of esophageal epithelium was achieved at energy density settings of 9.7 to 29.5 J/cm 2 . In Phase II, 9.7 and 10.6 J/cm 2 produced no stricture, whereas more than 20 J/cm 2 produced a stricture in every case. In Phase III, 8-20 J/cm 2 resulted in 100% epithelial ablation. Five and 8 J/cm 2 spared the muscularis mucosae, whereas 10 J/cm 2 caused injury to the muscularis mucosae but preserved the submucosa. In Phase IV, histologic examination demonstrated full-thickness epithelial removal in areas of electrode contact. Ablation extended only to the muscularis mucosae, without injury to submucosa. CONCLUSIONS In the porcine and the human esophagus, circumferential, full-thickness ablation of epithelium without direct injury to the submucosa is possible and was well tolerated. In all cases, depth of ablation was linearly related to energy density of treatment.

Diagnosis and monitoring of Whipple disease by polymerase chain reaction.

Whipple disease is a systemic bacterial infection with such protean clinical manifestations as diarrhea; abdominal pain; fever; lymphadenopathy; chronic arthralgias; weight loss; and, occasionally, central nervous system involvement that may include dementia, lethargy, and motor and sensory deficits [1-3]. At the time of diagnosis, most patients present with weight loss, diarrhea, and abdominal pain. Recognition of bacillary organisms in a small-bowel biopsy specimen that are positive on periodic acid testing and negative on acid-fast testing leads to the correct diagnosis. However, patients sometimes present with symptoms for which small-bowel biopsy is not usually done. Systemic manifestations, such as pleuritis, lymphadenopathy, cardiac valvular lesions, fever, and wasting may precede gastrointestinal symptoms [1, 2]; symptoms of arthritis may begin years before Whipple disease is diagnosed [2]. Patients with extraintestinal Whipple disease may present with involvement of the central nervous system or the eye [3-6]. Thus, the disease may remain undiagnosed in many patients who never develop gastrointestinal involvement; patients may also receive other diagnoses, such as rheumatoid arthritis or sarcoidosis, in the intervening period. The greatest challenge is to diagnose cases that appear to be clinically consistent with Whipple disease but for which a histologic diagnosis is either negative or equivocal. Because Whipple disease is uncommon, formal prospective evaluations of therapeutic regimens have not been done. Empirical antibiotic therapy with trimethoprim-sulfamethoxazole, cephalosporins, penicillins, or tetracyclines has varied in duration and outcome. In a case series of 29 patients with Whipple disease, the duration of treatment ranged from 5 days to 4 years [2]. Alleviation of symptoms and correction of biochemical and pathologic abnormalities were not related to the duration of antimicrobial therapy. A review of antibiotic therapy in 88 patients with Whipple disease who had long-term follow-up suggested that clinical relapse occurs in as many as 35% of cases [7, 8]; the outcomes of treatment for relapse of disease at the central nervous system were particularly poor [2, 8]. No test for cure is available for Whipple disease, but the recent identification of the 16S ribosomal RNA (rRNA) of the Whipple-associated bacillus, Tropheryma whippelii, has led to the use of 16S rDNA primers for detection of this organism on polymerase chain reaction (PCR) [9, 10]. Polymerase chain reaction assays with high sensitivities have shown T. whippelii in tissues that show no evidence of disease [9]. In this study, a PCR-based test for the detection of T. whippelii was evaluated. Our results suggest that PCR may be useful for the diagnosis of Whipple disease and for monitoring patients who have been treated with antibiotics, thereby allowing the physician to better direct the duration of antibiotic therapy and, perhaps, predict clinical relapse. Methods Patients Thirty patients who received a diagnosis of Whipple disease at the Mayo Clinic between 1952 and 1994 were identified through a computerized search of a diagnosis database. Medical charts of these patients were reviewed. Characteristics of 29 of the patients have been reported elsewhere [2]. Tissue Samples Tissue samples embedded in paraffin blocks were retrieved from the archives of the Mayo Clinic tissue registry; one to seven samples were available from each patient. The anatomic origin of the samples included the small intestine, rectum, pancreas, liver, brain, spleen, and lymph nodes. Post-treatment biopsy specimens were available from 17 of the 30 patients. The medical records of these 17 patients were reviewed by a gastroenterologist who was blinded to the results of PCR and histologic review. All histologic sections were rereviewed in a blinded manner by one pathologist. In small-intestine specimens, the diagnosis of Whipple disease was confirmed on the basis of the following criteria: 1) presence of macrophages in the lamina propria that contained periodic acid-Schiff staining granules, 2) resistance of periodic acid-Schiff-positive granules to diastase, 3) distortion of villous architecture due to the expanded, infiltrated lamina propria, and 4) dilated lymphatic channels (in some instances). Tissue specimens from regions other than the small intestine were also tested for evidence of Whipple disease. Histologic criteria were the presence of foamy histiocytes with bacilli that were positive on periodic acid-Schiff staining and were resistant to diastase and, in tissues from lymph nodes, dilated sinusoids with a Swiss cheese appearance. A histologic section of the small bowel from 1 patient that had been read elsewhere was reexamined in the Mayo Clinics Department of Pathology to confirm the diagnosis; a whole-blood sample (500 micro L) was obtained from this patient after a week of therapy with trimethoprim-sulfamethoxazole. In addition to the 30 patients who had confirmed cases of Whipple disease, 8 patients who had presented with gastrointestinal symptoms and had had biopsy of the small intestine were identified by using a medical records database. Whipple disease had been considered in the differential diagnosis for all 8 patients before biopsy of the small intestine was done. Biopsy specimens were classified as suspicious for or negative for Whipple disease. Medical charts on 7 patients were available for review. Paraffin-embedded biopsy specimens from the small intestine, colon, and brain of 42 patients who had malabsorption of undetermined cause, the irritable bowel syndrome, or viral encephalitis were used as controls. No histologic evidence of Whipple disease was found in these tissues, and all were negative for periodic acid-Schiff-positive macrophages. The control specimens were processed, interspersed with, and tested in a blinded manner in parallel with specimens from the 37 patients described above. Preparation and Analysis of Specimens We extracted two sections of formalin-fixed, paraffin-embedded tissue, each 25 m thick, that had been obtained from each patient. We used a new section of the knife for each cut to avoid cross-contamination during processing. Sections were deparaffinized with xylene and digested overnight at 55 C with 50 L of proteinase K (20 mg/mL) and sodium dodecyl sulfate (10%) in Tris (10 mmol/L) and EDTA (1 mmol/L). The digested tissue was boiled for 15 minutes to inactivate the proteinase K. Deoxyribonucleic acid was extracted by using a chaotropic lysis method with 200 L of the tissue (Isoquick kit, Orca Research, Bothell, Washington). Design of Primers Primers W3FE and W4RB were modified to improve their specificity for T. whippelii [11]. Primers W3AF and W4AR were designed on the basis of 16S rRNA gene sequence alignments of related organisms so that the region of gene that was amplified would be unique to T. whippelii. The expected size of the W3AF and W4AR amplification product was 160 base pairs. Evaluation of Specificity of Primers W3AF and W4AR We determined the specificity of primers W3AF and W4AR by doing PCR on DNA that had been extracted from clinical isolates of many bacteria: Nocardia brasiliensis, N. otitidiscaviarum, N. asteroides, Mycobacterium tuberculosis, M. kansasii, M. chelonae, M. bovis, M. fortuitum, M. avium-intracellulare complex, Actinomyces bovis, A. viscosus, anaerobic Actinomyces species, Corynebacterium species, Propionibacterium species, Rhodococcus equi, unspeciated Rhodococcus, and Streptomyces griseus. Amplification products were found only in R. equi and N. otitidiscaviarum. Sequencing of amplification products of these two organisms showed four variances in nucleotide bases compared with the T. whippelii sequence: C to T at position 1092, G to A at position 1093, C to T at position 1096, and G to A at position 1098. To ensure specific detection of T. whippelii, an 18-mer oligonucleotide probe homologous to T. whippelii sequence was designed to encompass the four-nucleotide variance (see Appendix Table (Table 5)). Table 5. Appendix Table. Sequence of Polymerase Chain Reaction Primers and 16S Ribosomal RNA Positions Relative to Escherichia coli Position 1 Primers W3FE and W2RB, which are also specific for T. whippelii, were used in accordance with the methods described elsewhere [9, 12]. Extraction Control We used the -globin gene, which is found in all nucleated cells, to assess the efficiency of the extraction of DNA from tissue. Tissue samples that were negative for Whipple-associated bacillus 16S rDNA products were amplified for a segment of the human -globin gene. Samples that did not have a positive result when tested for -globin were considered inadequate. Primers GH20 and PCO4 were used for -globin amplification [13]. Polymerase Chain Reaction with Primers W3AF and W4AR An amplification reaction mix, 45 L, was prepared from 10 L of 50% glycerol (10% final concentration), 5 L of 10 x Perkin-Elmer buffer (containing 100 mmol of Tris-HCl per L [pH, 8.3] [Sigma, St. Louis, Missouri], 500 mmol of KCl per L, and 15 mmol of MgCl2 per L) (Applied Biosystems, Perkin-Elmer, Foster City, California), 2 L each of the four deoxyribonucleoside triphosphates, 0.25 units of AmpliTaq polymerase (Applied Biosystems, Perkin-Elmer), 5 pmol of primers W3AF and W4AR, 0.33 L of isopsoralen (25 g/mL), and 19.42 L of sterile water. We added 10% or 5 L of extracted DNA from the specimen to this master mix for a final reaction volume of 50 L. Thermocycling was done as follows. Initial melting was done at 94 C for 2 minutes. This was followed by 50 cycles of denaturing at 94 C for 30 seconds, annealing at 60 C for 45 seconds, and extension at 72 C for 60 seconds. Final extension was done at 72 C for 4 minutes. After each amplification, the microtubes were exposed to ultraviolet light to promote covalent crosslinking of the isopsoralen [14]. This process prevents PCR product contamination, which can

Increased bile duct complications in liver transplantation across the ABO barrier.

ObjectiveThis study evaluated the outcome of liver grafts from ABO incompatible donors, focusing on biliary complications, and compared the results to an ABO compatible control group. Also, the expression of donor ABH antigens in the liver graft was analyzed. Summary Background DataThe outcome of liver transplantation using an ABO incompatible graft is still debated. These blood group related (ABH) antigens are known to be expressed not only on the surface of the erythrocytes, but also on the epithelial cells of large bile ducts. Because the biliary epithelium of hepatic altografts may continue to express donor ABH antigens, it may be more susceptible to immunologic bile duct injury after transplantation across the ABO barrier. MethodsEighteen ABO incompatible grafts were compared with 18 ABO compatible grafts in patients who were matched according to medical urgency, primary liver disease (PLD), and recipient age. After transplantation, the grafts were analyzed with cholangiography, Doppler ultrasound, or arteriography and liver histology according to protocol. Immunoperoxidase staining for ABH antigens was performed on hepatic tissue. ResultsBiliary complications developed in 82% of the ABO incompatible donors, compared to 6% of the ABO matched controls. Hepatic artery thrombosis occurred in 24%. Cellular rejection was diagnosed in 65% versus only 28% in the control group. The 1-year actuarial graft survival rate was 44% versus 78% in the control group. ABH antigens of the donor were expressed on vascular endothelium and bile duct epithelial cells as long as 150 days after transplant. ConclusionsUsing ABO incompatible allografts, a high incidence of biliary and hepatic artery complications and decreased graft survival in liver transplantation were found. An immunologic injury to the bile duct epithelium and/or to vascular endothelium is suspected.

The nature and prognostic implications of autoimmune hepatitis with an acute presentation

To determine the nature and prognostic implications of autoimmune hepatitis with an acute presentation, 12 patients with a disease duration of 3 months or less (mean duration, 2.3 +/- 0.2 months) were compared to 14 patients with a disease duration of 12 months or more (mean duration, 15.1 +/- 0.9 months). Liver tissue specimens were graded under code for lobular, portal and architectural changes. Patients with acute and chronic presentations were indistinguishable by age, sex, human leukocyte antigen phenotype, immunoserologic markers, and biochemical indices of liver inflammation. Moderate to severe lobular hepatitis was present more frequently in patients with acute presentations (75% versus 29%, p = 0.2), but differences were not statistically significant. Bridging fibrosis and cirrhosis were seen with equal frequency in both groups (79% versus 73%). Remission, relapse, treatment failure, progression to cirrhosis, and death from hepatic failure occurred with similar frequencies in patients with acute and chronic presentations. We conclude that autoimmune hepatitis with an acute presentation is indistinguishable by clinical and laboratory features from that with a chronic presentation and it is probably a pre-existent subclinical disease that is unmasked by disease progression or an abrupt exacerbation. Lobular hepatitis is an important histologic feature regardless of disease duration. The response to corticosteroid therapy is unaffected by the perceived duration of disease prior to treatment.

Lymphoepithelial Cysts of the Pancreas: a Report of 12 Cases and a Review of the Literature

Lymphoepithelial cyst (LEC) of the pancreas is a rare lesion of undetermined pathogenesis that had been documented almost exclusively in males. The literature on this entity is limited to reports of single or small numbers of cases. Here is presented a clinicopathologic analysis of 12 patients with LEC, 4 of whom were female. The mean age of the patients was 56 years. Four patients presented with abdominal pain and nausea, but in two patients, the cysts were detected incidentally. Only one patient had a history of chronic pancreatitis, and another had a family member with pancreatic cancer. In one patient, a clinical diagnosis of pseudocyst was rendered, and the remaining patients were clinically thought to have cystic neoplasms. None of the patients had any identifiable immunosuppression, HIV positivity, autoimmune disorder (such as Sjogren syndrome) or lymphoma. Seven cysts were located in the head of the pancreas, and 5 were in the tail. The mean size was 4.8 cm (range, 1.2–17 cm). Five LECs were multilocular, three were unilocular; in others, the number of loculi was not recorded. All were “macrocystic” lesions. Two patients had two separate lesions, both in the tail of the pancreas. Histologically, all cases were characterized by cysts, some containing keratin, and lined by mature stratified squamous epithelium surrounded by dense lymphoid tissue, often with prominent follicles. In some areas, the lining epithelium had more cuboidal, flattened, or transitional appearance. Mucinous goblet-like cells were seen in one case. Acute inflammation was not seen. Four cases contained solid lymphoepithelial islands, a feature not previously described in LECs. No squamous metaplasia was identified in the uninvolved pancreatic tissue and no epithelial elements were identified in peripancreatic lymph nodes. In summary, LEC of the pancreas is a rare but distinctive lesion that may be seen in the tail of the organ where most cystic pancreatic neoplasms are encountered. In contrast to the impression from the literature, LECs may also develop in females and, therefore, should be considered in the clinical differential diagnosis of mucinous cystic neoplasms that affect a similar age group. LECs are not associated with the clinical syndromes that are seen with their analogues in the salivary glands.